A variety of retinal degenerative diseases with retinal neuronal cell death are a major cause of blindness. That is, functional visual loss such as decrease in visual acuity and defect in the visual field is caused by degeneration and loss of the retina and optic nerves due to persistent or acute ocular hypertension, ischemia, and inflammation. Usually, the retina and optic nerves do not regenerate. Therefore, it is extremely difficult to regain the lost function.
Particularly, primary open-angle glaucoma is a leading cause of blindness in industrialized countries. Intraocular pressure-lowering therapy based on medication or laser trabeculoplasty has been performed. However, it is possible to slow the progression of glaucoma, but the prevention and improvement in the progress are still difficult. Particularly, acute primary angle-closure glaucoma shows rapid and high functional visual loss and has a high risk of blindness. Although early intraocular pressure-lowering therapy is performed, satisfied treatment results are currently not achieved. Recently, normal tension glaucoma has received attention because of increased morbidity. Although intraocular pressure-lowering therapy is effective in the case, prevention of progression has not been achieved. Since circumstances of the glaucomatous treatment are described above, there is a need of a novel pharmacotherapy which does not depend on intraocular pressure which is the cause of glaucoma.
The number of patients with age-related macular degeneration is increasing as the aging of society. In the treatment of exudative age-related macular degeneration, choroidal neovascular vessels are destroyed with laser beam. However, the treatment cannot be applied to the central part of the macula lutea and thus there is a need of a novel pharmacotherapy.
Further, photocoagulation is performed for branch retinal vein occlusion (BRVO), central retinal vein occlusion (CRVO), diabetic retinopathy and diabetic maculopathy. Although the proliferation of neovascular vessels is suppressed, the inflammation and circulatory disorder of retina are induced and decreased visual acuity is easily caused, which is a concern. Additionally, in vitreous surgery for severe maculopathy and severe proliferative retinopathy, a rapid ischemic reperfusion state is caused by the surgery. Visual recovery is not observed or is significantly delayed, which is bothering clinicians and patients. For these reasons, there is a need of a novel pharmacotherapy which prevents deterioration in visual function due to ophthalmic surgical treatment.
On the other hand, the present applicant has found (2S,4S)-6-fluoro-2′,5′-dioxospiro[chroman-4,4′-imidazolidine]-2-carboxamide (generic name: Fidarestat), i.e, a potent aldose reductase (AR) inhibitor. The compound has been developed as a compound which ensures high safety even if it is administered over long periods. Currently, its effect as a therapeutic agent for diabetic neuropathy has been studied in clinical trials.
With reference to the hydantoin derivative including fidarestat, the application to diabetic neuropathy is described in Japanese Patent Application Laid-Open (JP-A) No. 61-200991, the application to circulatory system disease is described in JP-A No. 4-173791, the application to age-related diseases is described in JP-A No. 6-135968, the application to simple diabetic retinopathy is described in JP-A No. 7-242547, the application to diabetic keratopathy is described in JP-A No. 8-231549, the application to diabetic maculopathy is described in WO2005/072066, the application to severe diabetic retinopathy is described in WO2005/079792, and the application to impaired cardiac function or myocardial damage resulting from ischemia or ischemia reperfusion is described in WO2006/090699. However, the use of the compound as the protective agent for retinal nerve or optic nerve is completely unknown. Further, the use of other aldose reductase inhibitors as the protective agent for retinal nerve or optic nerve has not been reported.    [Patent document 1] JP-A No. 61-200991    [Patent document 2] JP-A No. 4-173791    [Patent document 3] JP-A No. 6-135968    [Patent document 4] JP-A No. 7-242547    [Patent document 5] JP-A No. 8-231549    [Patent document 6] WO2005/072066    [Patent document 7] WO2005/079792    [Patent document 8] WO2006/090699